Live from London: LRI Research Director Jennifer Bell, PhD

Volcanic ash and high winds brought Barack Obama to a stand-still in the UK this week, but not me. I’m feeling slightly smug as I bypass the airport and sip my latte on the fast train from Edinburgh to London, on my way to the Annual European Congress in Rheumatology (aka EULAR).

Some 16,000 plus rheumatologists, physicians, researchers and patients will converge at London’s ExCeL center over the next 3 days (volcanic ash permitting). The packed program covers the full range of rheumatic diseases, from to anti-phospholipid syndrome to vasculitis.

For the next 3 days, however, I will be homing in on what is new in lupus.

You can follow my EULAR news and comment feed here on the LRI website, on Facebook, or on Twitter @sci_jen.

I’ll be looking out for answers on the causes and biological mechanisms of lupus, progress in lupus clinical trials and treatments, and new insights from the clinic.

And although I may have just missed Obama I’ll be catching up with LRI researchers Drs Jane Salmon and Theresa Lu to find out about their latest results.

Strategy for Cancer = A Strategy for Lupus?

Drugs that block the growth of new blood vessels can successfully stem cancer growth.

Could the same strategy work in inflammatory diseases such as lupus?

A EULAR session was dedicated to this question on Wednesday, chaired by Dr. Theresa Lu (Hospital for Special Surgery, New York, a two-time LRI grant holder).

In infections and during lupus flares, immune responses are triggered in lymph nodes. The nodes expand up to 10-times their regular size due to a network of new blood vessels that allow cells, nutrients and oxygen to flood into the node, fuelling a proliferation of white blood cells.

So could we treat or even prevent lupus flares by targeting new blood vessel growth (a process known as angiogenesis)?

Dr. Lu thinks lymph node blood vessels might be amenable to drug intervention, even mid-flare. She previously showed, in LRI-funded work, how specific cells and molecules coordinate the development and maintenance of new lymph node blood vessels.

Strategy Tested

In a mouse model of lupus, Dr. Lu has now tried inhibiting one factor involved in angiogenesis (VEGF). The lymph node blood vessel network disappeared, but only temporarily, and the disease persisted.

She is now trying other factors and is upbeat. “The field is booming,” she said, “and I am confident that we will find ways to either prevent or disrupt lymph node angiogenesis in a sustained manner.”

Live from London, Thursday May 26:

New Ideas on the Cause and Development of Lupus (Pathogenesis)

A EULAR session on Thursday 26th May focused on emerging ideas on how the lupus immune system turns on the body. Here are some highlights.

Autoantibody-producing cells are established early in life

Potentially dangerous autoantibodies can be found in the blood of people with lupus many years before their disease appears, but we know little about the source of those early autoantibodies.

On Thursday, Dr. Bimba Hoyer (Charité University Hospital, Berlin) presented new data showing that cells pumping out autoantibodies (plasma cells) appear in lupus-prone mice when they are just a few weeks old--months before the mice get sick.

These autoantibody factories are exceptionally stable and can persist for months to years in ‘survival niches’ in the bone marrow and spleen, making them a potentially tough target for therapy.

In lupus, kidney damage is caused by autoantibodies produced by immune system cells that have gathered in the kidney.

In 2008, Reinhard Voll and colleagues at the University of Erlangen-Nuremberg reported that a drug used to treat multiple myeloma--bortezomib (Velcade)--was effective against lupus in mice. This discovery has led to a Phase IV clinical trial in lupus nephritis.

On Thursday, Dr. Charlotte Starke from the Voll group presented new data showing that this drug might work by selectively eliminating antibody-producing cells in the kidneys.

Dr. Starke and colleagues found two types of autoantibody-producing cells in kidneys with lupus inflammation: short- and long-lived ones. Both cell types were eliminated by short-term treatment with bortezomib.

Autoantibody-producing cells at other sites in the body were untouched, as were B cells (the parent cells of antibody producing cells).

The bottom line: specific elimination of autoantibody-producing cells in the kidney might explain the benefits of bortezomib in cases of lupus nephritis.

Researchers are discovering that costimulatory molecules—receptors that deliver critical activating signals to immune system cells—offer great potential for new lupus therapies. At least four biologic inhibitors of costimulatory receptors are currently in clinical trials.

One of the newest costimulatory molecules to attract attention in lupus is the receptor PD1. On Thursday, Dr. Maida Wong from Dr. Bevra Hahn's group at the University of California in Los Angeles presented data showing that lupus-like disease in mice is improved by treatment with an antibody that blocks PD1.

The PD1-blocking antibody might work, in part, by boosting the function of specialized T cells known as regulatory T cells, which in turn dampen autoimmune responses.

Although their work is still at an early stage, Wong and colleagues believe it shows that PD1 could be targeted to control lupus autoimmunity.

New Lupus Treatments: The Tour

“A graveyard for drugs” was how EULAR President, Professor Paul Emery, described lupus yesterday as he reflected on the past 10 years in rheumatology.

But Dr. Jane Salmon (Hospital for Special Surgery, New York—and an LRI grant recipient) is more optimistic about future lupus therapies.

“Right now we have a very broad portfolio of potential therapeutic targets and interventions, from simple vitamin D to complex tolorogenic peptides,” said Jane. “And we have life experience in biologics”.

I met with Jane today at the end of the guided tour of scientific posters on lupus treatments, which she co-chaired with Dr. Edward Vital.

Highlights from the poster tour:

Dr. Dick De Vries (from Centocor, a Philadelphia biotechnology company) presented results from a Phase I trial of CNTO-136 in systemic and cutaneous (skin) lupus. The drug, a biologic inhibitor of an inflammatory molecule known as interleukin-6, had a good safety profile and indications that it may help lupus signs and symptoms. Patient recruitment is now underway for a Phase II trial.

Dr, Murray Urowitz (University of Toronto) reported the outcome of a Phase II study in lupus of Edratide, a peptide that modulates the immune system. The drug, which acts on regulatory T cells, failed to meet the primary endpoints of the trial. But there were some positive signals and the safety profile is good. The trial sponsor is planning a second Phase II trial.

Dr. Abou-Raya (University of Alexandria, Egypt) and colleagues have found that vitamin-D deficiency is prevalent in lupus patients. In a randomized placebo-controlled trial in people with lupus they found that certain disease markers were improved by supplementation with vitamin D.

Live from London, Friday May 27:

Lessons from EULAR 2011: The glass is no longer half-empty!

After three days of navigating the behemoth congress in search of new insights on lupus I came home with a stack of business cards, a mass of notes, and sore feet.

So what have I learned?

First: the possibilities for new lupus therapies have never looked better

There are over two-dozen targeted therapies currently in lupus clinical trials—and companies as well as scientists agree: there is a real chance that some will succeed.

The expectation is not that any one drug will prove to be a panacea, but that different drugs will be useful in treating different facets of the disease.

Therapies in the spotlight at this meeting:

B cell depletion biologics

blockers of interferon-alpha

blockers of interleukin-6

immunomodulators (products that re-direct rather than block the lupus immune system).

Second: more research on the mechanisms of lupus is critical if targeted therapies for the disease are to succeed

As Dr. Jane Salmon, an LRI researcher from New York City’s Hospital for Special Surgery put it: “We have a broad portfolio” of interventions, but we “have to understand in more depth and precision the critical pathways by which B cells generate autoantibodies” [those destructive antibodies that attack the body’s own cells, tissues, and proteins].

A case in point: Dr. Fabienne Mackay (Monash University, Melbourne, Australia) showed that the B cell growth factor targeted by the recently approved lupus drug belimumab (Benlysta™) might have a protective as well as a disease-promoting role in laboratory mice with lupus.

Third: there is a new energy in the lupus field

My final take-home message—and this is entirely subjective—is that there is a new sense of purpose and excitement across the lupus field.

The main lupus sessions packed out the largest auditorium, with standing room only in smaller sessions.

It seems pharmaceutical company scientists and researchers from other disciplines want to know what is happing in lupus research In part, this is likely due to the impact of a drug finally getting approval for use in lupus—the “Benlysta™” effect—but there also is a lot of new science to get excited about.

In terms of treatments and investment, lupus remains the poor relation in the rheumatic diseases family. But compared to the not-so-distant past, the glass now looks half-full rather than half-empty.

And as Dr. Frederic Houssiau (Belgium) said, with typical European moderation, “Keep filling the glass with good basic and clinical research. It will always remain half full…if not full.”

The next European Congress in Rheumatology is next June in Berlin: EULAR 2012!